Cytochrome oxidase C defects could be a biomarker for cancer screening. To see if the 2nd part of Warburg’s 1924 was correct (“defective mitochondrial function causing cells to be tumorigenic”), the Penn team took cell lines from the skeleton, kidney, breast and esophagus and used RNA molecules to silence the expression of select components of the mitochondrias’ cytochrome oxidase C, or CcO, a critical enzyme involved in oxidative phosphorylation. CcO uses oxygen to make water and set up a transmembrane potential that is used to synthesize ATP (energy source).
The biologists observed disrupting a single protein subunit of cytochrome oxidase C led to major changes in the mitochondria and cells themselves.”These cells showed all the characteristics of cancer cells,” Avadhani said. They displayed changes in their metabolism, becoming more reliant on glucose and reducing synthesis of ATP. Instead of oxidative phosphorylation, they largely switched over to #glycolysis, a less efficient means of making ATP that is common in cancer cells.
The cells lost contact inhibition and gained an increased ability to invade distant tissues. When they were grown in a 3D medium, which closely mimics the natural environment in which tumors grow in the body, the cells with disrupted mitochondria formed large, long-lived colonies, akin to tumors.
The researchers also silenced cytochrome oxidase C subunits in an already-tumorigenic breast and esophageal cancer cell lines. “We found that the cells became even more invasive, heightening their malignant potency,”
Finally the Penn team looked at actual tumors from human patients and found that the most oxygen-starved regions, which are common in tumors, contained defective versions of cytochrome oxidase.
>>Disrupting CcO triggered mitochondria to activate a stress signal to the nucleus, akin to an “SOS” alerting the cell that something is amiss. Avadhani’s team will examine whether inhibiting components of this mitochondrial stress signaling pathway might be a strategy for preventing cancer progression. “We are targeting the signaling pathway, developing a lot of small molecules and antibodies,” .. “Hopefully if you block the signaling the cells will not go into the so called oncogenic mode and instead would simply die.” In addition, looking for defects in cytochrome oxidase C could be a biomarker for cancer screening. http://www.upenn.edu/pennnews/news/disrupting-cells-powerhouses-can-lead-tumor-growth-penn-study-finds
Disrupting the function of the mitochondria (panels on right) made cells highly invasive compared to control cells.
Credit: Image courtesy of University of Pennsylvania
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